Project Summary: Risk of sporadic cancer in humans and animals varies greatly due to polymorphism of multiple genes, which are largely unknown. Identification of cancer susceptibility genes in the mice will permit to define their human homologues and their role in individual cancer risk. Until now in mouse models cancers in different organs were believed to be controlled by different genes. However, the large number of susceptibility genes for colon (Sec) and lung (Slue) cancer defined in this laboratory (15 and 30, respectively) allowed us to uncover an unexpected relationship between them. We found that Sec and Slue loci frequently co-localize in the same region. This pair-wise association of the Sec and Slue loci is not compatible with their expected independent distribution (P = 0.0036). This finding suggests that the two types of genes are either identical, or that they form at a number of genomic sites clusters of closely linked functionally related genes. Aims: We will determine rigorously the relationship between Sec and Slue genes by precision-mapping four Sec -Slue pairs and identifying their candidate gene(s). We will establish whether they are identical, and if not, we'll define the tightness of their linkage and degree of their similarity. This will be achieved by mapping both lung and colon tumor susceptibility to successively shorter genomic segments. The mosaic structure of the mouse genome, defined in our strains by more than 15,000 microsatellite and SNP markers, will help to locate the Sec - Slue genes to very short genomic segments. Genes in these segments will be screened by a number of molecular and functional criteria (polymorphism, expression pattern, effect on cell growth, somatic mutations in tumors) and the selected candidate gene will be validated by germ-line manipulation. We aim to identify one or more cancer susceptibility genes, but in addition we will contribute to understanding of across- organ control of cancer susceptibility. This will provide qualitatively novel information about the general and organ-specific control of tumorigenesis. Relevance: Human homologues of mouse cancer susceptibility genes are likely to influence individual risk of sporadic cancer. We identified previously Ptprj (Protein tyrosine phosphatase receptor type J) as candidate for mouse colon cancer susceptibility gene Seel. Recently PTPRJ was shown to control individual risk for sporadic breast cancer in humans. Moreover, two human susceptibility genes for colon and for lung cancer map very close to sites homologous to Slue genes. The probability of such apposition by chance is 0.04. This data strongly supports the importance of defining mouse tumor susceptibility genes as an approach towards definition of genetic risk of cancer in humans. If susceptibility genes for two or several frequent human cancers could be shown to be largely the same or clustered , as our mouse data suggest, rather than separate for each cancer type, their identification could be achieved faster and with much less effort.